rs4933977

Variant names:

• chr10-84205818-C-T
• rs4933977
• NM_033100.4:c.863-9C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033100.4(CDHR1):​c.863-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0499 in 1,609,556 control chromosomes in the GnomAD database, including 3,888 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (907 hom., cov: 32)
  • Exomes 𝑓: 0.046 (2981 hom.)
• Consequence: CDHR1 NM_033100.4 intron
• Scores: Splicing: ADA: 0.00002035
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.27
• Publications: 6 publications found

Genes affected

CDHR1 (HGNC:14550): (cadherin related family member 1) This gene belongs to the cadherin superfamily of calcium-dependent cell adhesion molecules. The encoded protein is a photoreceptor-specific cadherin that plays a role in outer segment disc morphogenesis. Mutations in this gene are associated with inherited retinal dystrophies. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2013]

CDHR1 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 15

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 65

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-84205818-C-T is Benign according to our data. Variant chr10-84205818-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033100.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDHR1	NM_033100.4	MANE Select	c.863-9C>T		intron	N/A	NP_149091.1	Q96JP9-1
	CDHR1	NM_001171971.3		c.863-9C>T		intron	N/A	NP_001165442.1	Q96JP9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDHR1	ENST00000623527.4	TSL:1 MANE Select	c.863-9C>T		intron	N/A	ENSP00000485478.1	Q96JP9-1
	CDHR1	ENST00000332904.7	TSL:1	c.863-9C>T		intron	N/A	ENSP00000331063.3	Q96JP9-2
	CDHR1	ENST00000926454.1		c.812-9C>T		intron	N/A	ENSP00000596513.1

Frequencies

GnomAD3 genomes AF: 0.0853 AC: 12972 AN: 152096 Hom.: 907 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.0942

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0738

GnomAD2 exomes AF: 0.0758 AC: 18935 AN: 249874 AF XY: 0.0703

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.0326

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.0193

Gnomad NFE exome AF: 0.0298

Gnomad OTH exome AF: 0.0556

GnomAD4 exome AF: 0.0462 AC: 67324 AN: 1457342 Hom.: 2981 Cov.: 30 AF XY: 0.0468 AC XY: 33967 AN XY: 725182

African (AFR) AF: 0.172 AC: 5732 AN: 33382

American (AMR) AF: 0.163 AC: 7260 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.0341 AC: 891 AN: 26096

East Asian (EAS) AF: 0.186 AC: 7373 AN: 39668

South Asian (SAS) AF: 0.0894 AC: 7688 AN: 85964

European-Finnish (FIN) AF: 0.0198 AC: 1058 AN: 53338

Middle Eastern (MID) AF: 0.0462 AC: 261 AN: 5648

European-Non Finnish (NFE) AF: 0.0304 AC: 33666 AN: 1108432

Other (OTH) AF: 0.0564 AC: 3395 AN: 60236

GnomAD4 genome AF: 0.0853 AC: 12991 AN: 152214 Hom.: 907 Cov.: 32 AF XY: 0.0860 AC XY: 6399 AN XY: 74418

African (AFR) AF: 0.167 AC: 6940 AN: 41522

American (AMR) AF: 0.127 AC: 1945 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 129 AN: 3472

East Asian (EAS) AF: 0.194 AC: 1000 AN: 5166

South Asian (SAS) AF: 0.0929 AC: 448 AN: 4824

European-Finnish (FIN) AF: 0.0180 AC: 191 AN: 10618

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0309 AC: 2104 AN: 68018

Other (OTH) AF: 0.0769 AC: 162 AN: 2108

Alfa AF: 0.0509 Hom.: 580

Bravo AF: 0.0970

Asia WGS AF: 0.138 AC: 477 AN: 3478

EpiCase AF: 0.0306

EpiControl AF: 0.0325

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cone-Rod Dystrophy, Recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.6
DANN	Benign	0.70
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4933977; hg19: chr10-85965574; COSMIC: COSV60564886; COSMIC: COSV60564886;